This is an RO3 application to investigate a new protein discovered and characterized by the applicant, called deltaBAFF. DeltaBAFF is a novel splicing isoform of the B cell regulator BAFF, a TNF-family protein with powerful immunoregulatory effects. Over-expression of BAFF leads to excessive B cell accumulation, activation, autoantibodies, and lupus-like disease, whereas an absence of deltaBAFF causes peripheral B cell immunodeficiency. It is important to understand how the balance between BAFF-mediated B cell survival and autoimmunity is controlled. The idea that deltaBAFF plays a role in restraining the effects of BAFF and regulating B lymphocyte homeostasis will be tested. The effects of specifically altering the ratio of deltaBAFF to full-length BAFF expression in vivo by transgenesis will be tested. The effects of homomultimers or heteromultimers on membrane expression and biological function will be tested. The long-term goal of these studies is to understand B lymphocyte homeostasis. Understanding the function of deltaBAFF may provide clues to help us understand and cure autoimmune disease and B lymphoid cancer.